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Down modulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma

ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal overall survival (OS) and to date few molecular markers are available to guide patient management. This study aimed to identify a prognostic miRNA signature in MPM patients who did not undergo tumor resection. Whole miRNA profiling using a microarray platform was performed on 26 unresected MPM with distinct clinical outcome: 15 patients had aggressive disease (OS<12 months) and 11 patients indolent disease (OS>36 months). Three prognostic miRNAs (mir-99a, let-7c and miR-125b) encoded at the same cluster (21q21) were selected for further validation and tested on publicly available miRNA sequencing data (TCGA) from 72 MPM patients with survival data. A risk model was built based on these 3 miRNAs that was validated by quantitative PCR in an independent set of 30 MPM patients. High risk patients had shorter median OS (7.6 months) as compared with low-risk patients (median not reached). In the multivariate Cox model, a high risk score was an independently associated with shorter OS (HR=3.14; 95% CI, 1.18–8.34; P=0.022). Our study identified that the downregulation of the miR-99a/let-7/miR-125b miRNA cluster predicts poor outcome in unresected MPM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE92636 | GEO | 2017/07/28

SECONDARY ACCESSION(S): PRJNA358208

REPOSITORIES: GEO

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Project description:Background: Only a subset of radically-resected pancreatic ductal adenocarcinoma (PDAC) patients benefit from chemotherapy, and identification of novel prognostic factors is warranted. Recently miRNAs emerged as diagnostic biomarkers and innovative therapeutic targets, while high-throughput arrays are opening new opportunities to evaluate whether they can also predict clinical outcome. The present study evaluated whether comprehensive miRNA expression profiling correlated with overall survival (OS) in resected PDAC patients. Methodology/Principal Findings: High-resolution miRNA profiles were obtained with the Toray’s 3D-GeneTM miRNA chip, detecting more than 1200 types of human miRNA. RNA was isolated from paraffin-embedded primary tumors of 26 radically resected stage-pT3N1 homogeneously treated patients (adjuvant gemcitabine 1000mg/m2/day, days-1/8/15, every 28days), carefully selected according to their outcome (OS<12 vs. OS>30 months, i.e. short/long-OS). Highly stringent statistics included t-test, distance matrix with Spearman-ranked correlation, and iterative approaches. Unsupervised hierarchical analysis revealed that PDAC specimens clustered according to their short/long-OS classification, while the feature selection algorithm RELIEF identified the top-4 discriminating miRNAs between the two groups. These miRNAs target more than 1500 transcripts, including 169 targeted by two or more of these miRNAs. MiR-211 emerged as the best discriminating miRNA, with significantly higher expression in long- vs. short-OS patients. The expression of this miRNA was subsequently assessed by quantitative-PCR in an independent cohort of laser microdissected tumors from 60 resected stage-pT3N1 PDAC patients treated with the same gemcitabine regimen. Patients with low miR-211 expression according to median value had a significantly shorter median OS (14.8, 95%CI=13.1-16.5, vs. 25.7 months, 95%CI=16.2-35.1, log-rank P=0.004). Multivariate analysis demonstrated that low miR-211 expression was an independent factor of poor prognosis (hazard ratio 2.3, P=0.03) after adjusting for all the factors influencing outcome.

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Down modulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma

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